Compliant tissue sealants

ABSTRACT

An improved barrier or drug delivery system which is highly adherent to the surface to which it is applied is disclosed, along with methods for making the barrier. In the preferred embodiment, the system is compliant, in that it is capable of conforming to the three dimensional structure of a tissue surface as the tissue bends and deforms during healing processes. The barrier or drug delivery systems is formed as a polymeric coating on tissue surfaces by applied a polymerizable monomer to the surface, and then polymerizing the monomer. The polymerized compliant coating preferably is biodegradable and biocompatible, and can be designed with selected properties of compliancy and elasticity for different surgical and therapeutic applications.

BACKGROUND OF THE INVENTION

[0001] This application is a continuation-in-part of PCT InternationalApplication No. PCT/US 96/03834, filed Mar. 22, 1996, the disclosure ofwhich is incorporated herein.

[0002] The present invention relates to methods and compositions forimproving the adherence of polymer gels to surfaces, particularly tissuesurfaces, and for improving the compliance of the materials.

[0003] Locally polymerized gels have been used as barriers and drugdelivery devices for several medical conditions. Adherence of the formedgel to the tissue can be a problem, especially under surgicalconditions, where the tissue surface to be treated is typically wet, andmay further be covered with blood, mucus or other secretions. Hubbelland co-workers have described two methods for photopolymerizing gels incontact with tissue surfaces. In U.S. Pat. No. 5,410,016, herebyincorporated by reference, application of biodegradable macromers totissue, followed by photopolymerization to form a gel, is described. Twomethods for photopolymerizing gels are described. In “bulk”polymerization, a suitable photoinitiator and accessory reagents aresolubilized or dispersed in a solution of gelling macromers. Onapplication of light, the entire solution volume crosslinks to form agel which acts as a local barrier or drug depot. These gels havesubstantial adherence to most surfaces, including tissue surfaces whichare merely moist. However, if a confounding layer of fluid is present onthe surface when the macromer/initiator solution is applied, then thegel may delaminate from the surface after its formation.

[0004] An alternative way of forming a gel layer on a surface, asdescribed in U.S. Ser. No. 08/024,657, which is hereby incorporatedherein by reference, is called the “interfacial” method. In this method,the surface to be coated is treated with a photoinitiator which adsorbsor absorbs to the surface. After washing away excess, unabsorbedphotoinitiator, a polymerizable macromer solution is applied to thesurface. On exposure to light, polymerization is initiated at thesurface, and progresses outward into the solution to the limit ofdiffusion of the photoinitiator-generated radicals during theirlifespan. Coating thicknesses of up to about 500 micrometers (microns)are routinely obtained. Since they are in effect “grown” from the tissuesurface, such gel layers have excellent adhesion to the tissue surfaceunder difficult conditions, including the presence of thin layers offluid adherent to the surface. The limited thickness of such interfacialgels is desirable in some circumstances, but represents a majorlimitation where gels of substantially greater thickness than 500microns are required, for example, for use in drug delivery, or informing a thick physical barrier between the tissue surface and itssurroundings. In addition to the photopolymerizable gels described byHubbell et al. (WO 93/17669) and Sawhney et al., (J Biomed. Mats. Res.28, 831-838, 1994), systems for forming drug delivery depots or barrierson surfaces include the polymers described in U.S. Pat. No 4,938,763 toDunn, et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohn et al.,U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et al., and U.S. Pat.No. 4,511,478 to Nowinski et al. Use of preformed barrier materials suchas Goretex™ membrane (W. L. Gore) has been described in the literature.

[0005] Although all of these materials are suitable for application totissue and other substrates, adhesion is in many cases limited, or inthe case of the preformed barrier materials, essentially non-existent.

[0006] There are many situations in which the application of a polymericmaterial, or a polymerizable material followed by polymerization, is theappropriate or preferred method of sealing a tissue or organ to preventmigration of a fluid, such as blood or air, from or into the tissue ororgan.

[0007] Well-known materials for making such bonds arecyanoacrylate-based adhesives and fibrin glue. Cyanoacrylates arechemically related to familiar domestic adhesives such as “CrazyGlue™”.On contact with water, the cyanoacrylate residues spontaneouslypolymerize. The resulting resins are brittle, poorly biodegradable, andoften not biocompatible.

[0008] Fibrin glues are typically made by contacting a solution orsuspension of the blood protein fibrinogen with an enzyme or otherreagent which can crosslink it. Typically, the enzyme thrombin is used,which cleaves the fibrinogen molecule, forming fibrin monomer which thenspontaneously polymerizes. This is a natural reaction involved in theformation of blood clots. Fibrin glues often have better adherence totissues than do cyanoacrylates, and are rapidly biodegraded. However,like cyanoacrylates, they have little flexibility or elasticity oncetheir deposition is complete. A familiar example of a crosslinkedfibrin-based material is a scab or an eschar.

[0009] Neither fibrin glues nor cyanoacrylates are stretchable, oncepolymerized. It is believed that this lack of compliance (i.e., highelastic modulus and low elongation at rupture) is an important reasonwhy seals formed with these and related prior-art materials are likelyto fail prematurely, especially when the area which is joined or sealedis subject to deformation.

[0010] Numerous materials are known and used in medicine which arehighly elastic, such as rubber gloves and flexible elastic bandages.However, such materials do not bind tightly to tissue, particularly tomoist tissue, which is required if the tissue is to be sealed.

[0011] It is therefore an object of the present invention to providemethods and compositions for enhancing the adhesion of polymericmaterials to tissue surfaces and other substrates.

[0012] It is a further object of the present invention to providemethods and compositions for increasing the thicknesses of polymericmaterials which can be “tethered” to a tissue surface or othersubstrates.

[0013] It is a further object of the present invention to provideimproved initiator systems for the formation of gels on tissues andother surfaces.

[0014] It is a further object of the present invention to provideimproved methods and new medical indications for the sealing and coatingof tissue.

[0015] It is another object of the invention to provide an improvedsealing material and method, characterized in that the sealant materialis compliant with tissue after its formation, as well as stronglyadherent to tissue.

[0016] It is a further object of the invention to provide kits for theformation of such compliant sealant materials.

SUMMARY OF THE INVENTION

[0017] An improved barrier, coating or drug delivery system which ishighly adherent to the surface to which it is applied is disclosed,along with methods for making the barrier. The barriers and coatingsformed by polymerization of polymerizable materials on the surface oftissue form barriers or coatings which are compliant with the tissue, aswell as adherent, i.e., are capable of conforming to the tissue. Thepolymerized coatings preferably are biocompatible and biodegradable.

[0018] In a preferred embodiment, tissue is stained with aphotoinitiator, then the polymer solution or gel in combination with adefined amount of the same or a different photoinitator is applied tothe tissue. On exposure to light, the resulting system polymerizes atthe surface, giving excellent adherence, and also forms a gel throughoutthe illuminated volume. Thus a gel barrier or coating of arbitrarythickness can be applied to a surface while maintaining high adherenceat the interface. This process is referred to herein as “priming”. Thepolymerizable barrier materials are highly useful for sealing tissuesurfaces and junctions against leaks of fluids. In the examplesdescribed below, the fluids are air and blood; however, the principle isalso applicable to other fluids, including bowel contents, urine, bile,cerebrospinal fluid, vitreous and aqueous humors and other fluids whosemigration within a living organism must be contained.

[0019] In another embodiment, “priming” can be used to reliably adherepreformed barriers or coatings to tissue or other surfaces, or to adheretissue surfaces to each other. A first surface and a preformed barrieror coating, or another surface, are prestained with initiator, and athin layer of polymerizable monomer containing initiator is placedbetween them. Strong adhesion is obtained between the two surfaces onpolymerization of the monomer. In a similar fashion, tissue surfaces canbe adhered to each other is in repair of wounds and formation ofanastomoses.

[0020] The priming method is suitable for any mode of polymerization.While especially effective in photopolymerization, chemical or thermalpolymerization can also be accomplished by this method. Further, anenhancement of photoinitiation can be achieved by adding suitable redoxinitiation components to the system, providing a new form oflight-controlled chemically accelerated polymerization reaction,especially effective in the presence of blood.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]FIG. 1 shows the stress vs. strain curve of a compliant sealantformed by photopolymerization of a poly(ethyleneglycol)-oligotrimethylene carbonate copolymer end capped with acrylateester.

DETAILED DESCRIPTION OF THE INVENTION

[0022] Materials with improved compliance, and methods for theirmanufacture and application to tissue are provided. In one embodiment,materials may be used which are described in PCT/US/96/03834, filed Mar.22, 1996, the disclosure of which is incorporated herein by reference.Polymerized barriers or coatings may be formed from polymerizableprecursor materials which can include, for example, crosslinkable orcurable molecules. A wide variety of precursor materials may be used,provided that they form cured or crosslinked materials having theproperties of biocompatibility and an appropriate elastic property, suchas a compliance ratio, as described in detail below. Preferably, thepolymerized materials are biodegradable. The compliant materials may beused as sealants, may contain biologically active materials, and be usedin drug delivery applications.

[0023] By selection of the appropriate polymerizable materials,polymeric compliant polymer coatings on tissue may be formed, and theproperties of the polymers may be altered to control the normalizedcompliance ratio of such polymers relative to that of a tissue.

[0024] Definitions

[0025] As used herein, the term “sealant” refers to a material whichdecreases or prevents the migration of fluid from or into a surface suchas a tissue surface. Sealants are typically formed by the application ofprecursor molecules to a tissue followed by local polymerization. Thesame materials may also be used to adhere materials together, eitherwhen applied between them and polymerized, or when used to jointly embedmaterials.

[0026] As used herein, the term “biocompatibility,” in the context ofbiologically-related uses, refers to the absence of stimulation of asevere, long-lived or escalating biological response to an implant orcoating, and is distinguished from a mild, transient inflammation whichtypically accompanies surgery or implantation of foreign objects into aliving organism.

[0027] As used herein the term “biodegradability” refers to thedisintegration, which is preferably predictable, of an implant intosmall entities which will be metabolized or excreted, under theconditions normally present in a living tissue.

[0028] The properties of the particular coating or barrier materialsdisclosed herein are referred to as “materials properties”, and include:

[0029] the “Young's modulus” (of elasticity) which is the limitingmodulus of elasticity extrapolated to zero strain;

[0030] the “elastic modulus” which is any modulus of elasticity, notlimited to Young's modulus, and may include “secant modulus” and otherdescriptors of non-linear regions of the stress-strain curve;

[0031] the “bulk” or “compressive” modulus which is used in its usualsense of ratio of stress to a designated compressive strain;

[0032] the “elongation at failure” which is the relative strain orextension of a test specimen at which any irreversible orhysteresis-inducing change occurs in the specimen; and

[0033] the “elongation at break” or “elongation at rupture” which is therelative strain (extension) of a test specimen at which mechanicalrupture occurs.

[0034] The term “compliance” as used herein is used in a general sense,and refers for example to the ability of an implant to closely match thephysiological and mechanical properties of tissues at the implant site,except when “compliance” is used in a specific technical sense as thereciprocal of a modulus.

[0035] As applied to a relatively thin, flat material such as a tissueor a layer of sealant, “normalized compliance” (NC) is defined herein asthe strain,(i.e., the elongation or compression per unit length of aspecimen), divided by the applied force per unit cross-sectional area,further divided by the thickness of the specimen. Hence, for a samplehaving a width w (for example, the width of the clamps of the testingapparatus), and a thickness t, when an applied force F produces a strainS, then the compliance C is$C = {\frac{S}{F/{wt}} = \frac{S\quad \cdot \quad {wt}}{F}}$

[0036] and the normalized compliance is${NC} = {\frac{C}{t} = {\frac{S}{F/w} = \frac{Sw}{F}}}$

[0037] i.e., the strain in the sample divided by the force per unitwidth applied to the sample. The normalized compliance allows directcomparison of the forces required to deform the tissue versus a coatingon the tissue, without regard to the relative thicknesses of thesematerials.

[0038] The normalized compliance ratio (abbreviated NCR) is defined asthe value of the normalized compliance of the tissue or other substratedivided by the normalized compliance of the sealant material. When bothmeasurements are conducted on strips of the same width and at the sameforce, the NCR is simply the ratio of the strains at a particular force.A low NCR (less than 1) is obtained when the sealant material is easierto deform than the tissue, while a high NCR (greater than 1) is obtainedwhen the tissue is easier to deform than the sealing material.

[0039] As used herein, the term “elastomer” refers to a polymericmaterial which at room temperature is capable of repeatedly recoveringin size and shape after removal of a deforming force. In someembodiments, an elastomer is a material which can be repeatedlystretched to twice its original length and will repeatedly return to itsapproximate length on release of the stress.

[0040] The phrase “elastomeric materials” is a phrase which has beenused in the literature. There are many publications describingstructure- property relationships of elastomers and other deformablematerials. Lower elastic modulus and, frequently, an increasedreversible elongation to break or fracture, are found when any of thefollowing occur:

[0041] 1. The distance between nodes or junctions or more crystalline(“hard”) segments increases.

[0042] 2. The crosslink density decreases. This may be controlled byamount of crosslinker, nature of crosslinker, and degree of cure, aswell as by segment length of either the crosslinked species or thecrosslinking species, where different.

[0043] 3. For a material at equilibrium with a continuous phase, anincrease in the plasticization of the elastomer by the continuous phase.For applications wherein the continuous phase is water, moreparticularly physiological saline, increasing hydrophilicity tends toincrease compliance.

[0044] In order to seal fluid leaks in tissue, the sealing material mustremain firmly bonded to the tissue during motions required of the tissueduring the healing process. For tissues and organs which cannot beimmobilized, such as the lung, an effective sealing material is bothtightly-adherent and compliant, having materials properties similar tothose of the tissue. Examples of compliant adherent materials andmethods for their construction and use are provided.

[0045] In one embodiment, one or more initiators are applied to asurface to form an absorbed layer. “Absorbed” is used herein toencompass both “absorbed” and “adsorbed”. A solution of polymerizablemolecules, referred to herein as “monomers”, is then applied.

[0046] Methods

[0047] In one embodiment, one or more initiators or components of aninitiation system are applied directly to the surface, and theunabsorbed excess is optionally removed by washing or blotting. Theinitiator solution may further contain one or more polymerizablemonomers, and other useful formulating ingredients, includingaccelerators, co-initiators, sensitizers, and co-monomers. Then a liquidcontaining polymerizable monomers in combination with one or moreinitiators or components of an initiation system, which may be the sameas or different from that absorbed in the first step, is applied. Thesystem, if not self-polymerizing, is then stimulated to polymerize, forexample by application of an appropriate wavelength of light.

[0048] The priming and monomer-application steps can also be combined.For example, if excess initiator is not removed before monomer addition,then subsequent application of monomer will result in mixture ofinitiator into the monomer layer. Similarly, if the monomer layercontains an initiator with a high affinity for the surface, then it ispossible to apply a monomer layer containing initiator, and wait anappropriate time to allow preferential absorption of the initiator tothe surface, to achieve the same effect.

[0049] All of these methods may collectively be described as applicationof the monomer in an “initiating-incorporating manner”, encompassing anymeans of application and mixing which results in both an absorbed layerof initiator, and a layer of monomer incorporating an initiator, beingpresent on a surface to be coated.

[0050] The initiators may be chemical, photochemical, or a combinationthereof. With non-photochemical systems, a reductant component and anoxidant component may be present in the two parts of the solution, i.e.,in the priming layer and the coating layer.

[0051] Alternatively, a two-step process can be used to form polymers,especially bioabsorbable hydrogels on tissue. In the first step thetissue is treated with an initiator or a part of an initiator system forthe polymerization of olefinic (e.g. acrylic) or other functionalmonomers, optionally with monomer in the priming solution. This providesan activated tissue surface. In the second step, monomer(s) and, ifappropriate, the remainder of an initiator system, are together placedin contact with the activated tissue, resulting in polymerization on thetissue. An example of such a system is the combination of a peroxygencompound in one part, and a reactive ion, such as a transition metal, inanother.

[0052] This process of spontaneous polymerization does not require theuse of a separate energy source. Moreover, since the process ofpolymerization is initiated when part one contacts part two, there areno “spot life” issues due to initiation of polymerization. If desired,part one or part two can contain dyes or other means for visualizing thehydrogel coating.

[0053] An example of a system that can be used in this method is thespontaneous “contact” initiator systems such as those found in two part“acrylic structural adhesives”. All components of the materials used asdescribed herein, however, must display biocompatibility as well as theability to spontaneously polymerize on tissue. The use of tributylborane for this purpose is illustrated here.

[0054] These systems can markedly simplify the delivery of gel totissue, especially in areas hard to reach or hold for a photochemicalsystem. The delivery system can be much simpler. Moreover, it has beendiscovered that a two-part chemical system such as a redox system andespecially one based on peroxygen, can be used to chemically enhance thecuring of a photochemical system, thereby combining the control of aphotochemical system with the ability of a chemical system to overcomecolored impurities, such as blood.

[0055] In one embodiment, as described in U.S. Pat. No. 5,410,016,biodegradable macromers are applied to tissue, followed byphotopolymerization to form a gel. In addition to the photopolymerizablegels described by Hubbell et al. (WO 93/17669) and Sawhney et al., (J.Biomed. Mats. Res., 28:831-838, 1994), systems for forming drug deliverydepots or barriers on surfaces include the polymers described in U.S.Pat. No. 4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and4,826,945 to Cohn et al., U.S. Pat. Nos. 4,741,872 and 5,160,745 to DeLuca et al., U.S. Pat. No. 5,527,864 to Suggs et al., and U.S. Pat. No.4,511,478 to Nowinski et al. These materials, which covalentlycross-link by free-radical-initiated polymerization, are preferredmaterials. However, materials which cross-link by other mechanisms, orwhich comprise low-molecular weight reactive monomers, are alsopotentially suitable if they are biocompatible and non-toxic.

[0056] Compositions

[0057] MONOMERS

[0058] Any monomer capable of being polymerized to form a surfacecoating can be used. The monomers may be small molecules, such asacrylic acid or vinyl acetate; or they may be larger moleculescontaining polymerizable groups, such as acrylate-capped polyethyleneglycol (PEG-diacrylate), or other polymers containingethylenically-unsaturated groups, such as those of U.S. Pat. No.4,938,763 to Dunn et al., U.S. Pat. Nos. 5,100,992 and 4,826,945 to Cohnet al., U.S. Pat. Nos. 4,741,872 and 5,160,745 to De Luca et al., orU.S. Pat. No. 5,410,016 by Hubbell et al. Properties of the monomer,other than polymerizability, will be selected according to the use,using principles as known in the art. There is an extensive literatureon the formulation of polymerizable coating materials for particularapplications; these formulae can readily be adapted to use the improvedadherence-promoting polymerization system described herein with littleexperimentation.

[0059] In the particular application area of coating of tissues, cells,medical devices, and capsules, formation of implants for drug deliveryor as mechanical barriers or supports, and other biologically relateduses, the general requirement of the coating materials arebiocompatibility and lack of toxicity. For all biologically-relateduses, toxicity must be low or absent in the finished state forexternally coated non-living materials, and at all stages forinternally-applied materials. Biocompatibility, in the context ofbiologically-related uses, is the absence of stimulation of a severe,long-lived or escalating biological response to an implant or coating,and is distinguished from a mild, transient inflammation whichaccompanies implantation of essentially all foreign objects into aliving organism.

[0060] The monomer solutions should not contain harmful or toxicsolvents. Preferably, the monomers are substantially soluble in water toallow their application in a physiologically-compatible solution, suchas buffered isotonic saline. Water-soluble coatings may form thin films,but more preferably form three-dimensional gels of controlled thickness.

[0061] It is especially preferable in cases involving implants that thecoating formed be biodegradable, so that it does not have to beretrieved from the body. Biodegradability, in this context, is thepredictable disintegration of an implant into small molecules which willbe metabolized or excreted, under the conditions normally present in aliving tissue.

[0062] The macro-monomers (“macromers”) which are covalentlycrosslinkable to form hydrogels preferably comprise a block copolymer.The macromers can be quickly polymerized from aqueous solutions. Themacromers may advantageously be capable of thermoreversible gelationbehavior, and may be polymerized from a solution state or from a gelstate.

[0063] Preferred monomers are the photopolymerizable, biodegradable,water-soluble macromers described by Hubbell et al. in U.S. Ser. No.08/022,687, the teachings of which are incorporated herein. Thesemonomers are characterized by having at least two polymerizable groups,separated by at least one degradable region. When polymerized in water,they form coherent gels which persist until eliminated byself-degradation. In the most preferred embodiment, the macromer isformed with a core of a polymer which is water soluble andbiocompatible, such as the polyalkylene oxide polyethylene glycol,flanked by hydroxy acids such as lactic acid, having coupled theretoacrylate groups. Preferred monomers, in addition to being biodegradable,biocompatible, and non-toxic, will also be at Least somewhat elasticafter polymerization or curing. Elasticity, or repeatablestretchability, is often exhibited by polymers with low modulus. Brittlepolymers, including those formed by polymerization of cyanoacrylates,are not generally effective in contact with biological soft tissue.

[0064] It has been determined that monomers with longer distancesbetween crosslinks are generally softer, more compliant, and moreelastic. Thus, in the polymers of Hubbell, et al., increased length ofthe water-soluble segment, such as polyethylene glycol, tends to givemore elastic gel, and these tend to adhere better, especially understretching (as when applied to lung). Molecular weights in the range of10,000 to 35,000 of polyethylene glycol are preferred for suchapplications, although ranges from 3,000 to 100,000 are useful.

[0065] In the discussion below and the examples, monomers of this kind,also called macromers, are often designated by a code of the form xxKZn.“xxK” represents the molecular weight of the backbone polymer, which ispolyethylene glycol unless otherwise stated, in thousands of daltons. Zdesignates the biodegradable linkage, where L is for lactic acid, G isfor glycolic acid, C is for caprolactone, and TMC is fortrimethylenecarbonate. N is the average number of degradable groups inthe block. The molecules are terminated with acrylic acid groups, unlessotherwise stated; this is sometimes also indicated by the suffix A2.

[0066] CROSSLINKABLE GROUPS

[0067] The monomers or macromers preferably include crosslinkable groupswhich are capable of forming covalent bonds with other compounds whilein aqueous solution. These crosslinkable groups permit crosslinking ofthe macromers to form a gel, either after, or independently fromthermally dependent gelation of the macromer. Chemically or ionicallycrosslinkable groups known in the art may be provided in the macromers.The crosslinkable groups in one preferred embodiment are polymerizableby photoinitiation by free radical generation, most preferably in thevisible or long wavelength ultraviolet radiation. The preferredcrosslinkable groups are unsaturated groups including vinyl groups,allyl groups, cinnamates, acrylates, diacrylates, oligoacrylates,methacrylates, dimethacrylates, oligomethoacrylates, or otherbiologically acceptable photopolymerizable groups.

[0068] Other polymerization chemistries which may be used include, forexample, reaction of amines or alcohols with isocyanate orisothiocyanate, or of amines or thiols with aldehydes, epoxides,oxiranes, or cyclic imines; where either the amine or thiol, or theother reactant, or both, may be covalently attached to a macromer.Mixtures of covalent polymerization systems are also contemplated.Sulfonic acid or carboxylic acid groups may be used.

[0069] Preferably, at least a portion of the macromers will becrosslinkers, i.e., will have more than one crosslinkable reactivegroup, to permit formation of a coherent hydrogel by ensuring thecrosslinking of the polymerized macromers. Up to 100% of the macromersmay have more than one reactive group. Typically, in a synthesis, thepercentage will be on the order of 50 to 95%, for example, 60 to 80%.The percentage may be reduced by addition of co-monomers containing onlyone active group. A lower limit for crosslinker concentration willdepend on the properties of the particular macromer and the totalmacromer concentration, but will be at least about 3% of the total molarconcentration of reactive groups. More preferably, the crosslinkerconcentration will be at least 10%, with higher concentrations, such as30% to 90%, being optimal for maximum retardation of diffusion of manydrugs. Optionally, at least part of the crosslinking function may beprovided by a low-molecular weight crosslinker. When the drug to bedelivered is a macromolecule, higher ranges of polyvalent macromers(i.e., having more than one reactive group) are preferred. If the gel isto be biodegradable, as is preferred in most applications, then thecrosslinking reactive groups should be separated from each other bybiodegradable links. Any linkage known to be biodegradable under in vivoconditions may be suitable, such as a degradable polymer block. The useof ethylenically unsaturated groups, crosslinked by free radicalpolymerization with chemical and/or photoactive initiators, is preferredas the crosslinkable group.

[0070] The macromer may also include an ionically charged moietycovalently attached to a macromer, which optionally permits gelation orionic crosslinking of the macromer.

[0071] HYDROPHILIC REGIONS

[0072] Water soluble hydrophilic oligomers available in the art may beincorporated into the biodegradable macromers. The hydrophilic regioncan be for example, polymer blocks of poly(ethylene glycol),poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone),poly(ethyloxazoline), or polysaccharides or carbohydrates such ashyaluronic acid, dextran, heparan sulfate, chondritin sulfate, heparin,or alginate, or proteins such as gelatin, collagen, albumin, ovalbumin,or polyamino acids.

[0073] BIODEGRADABLE REGIONS

[0074] Biodegradable molecules or polymers thereof available in the artmay be incorporated into the macromers. The biodegradable region ispreferably hydrolysable under in vivo conditions. In some embodiments,the different properties, such as biodegradability and hydrophobicity orhydrophilicity, may be present within the same region of the macromer.

[0075] Useful hydrolysable groups include polymers and oligomers ofglycolide, lactide, epsilon-caprolactone, other hydroxy acids, and otherbiologically degradable polymers that yield materials that are non-toxicor present as normal metabolites in the body. Preferredpoly(alpha-hydroxy acids) are poly(glycolic acid), poly(DL-lactic acid)and poly(L-lactic acid). Other useful materials include poly(aminoacids), polycarbonates, poly(anhydrides), poly(orthoesters),poly(phosphazines) and poly(phosphoesters). Polylactones such aspoly(epsilon-caprolactone), poly(delta-caprolactone),poly(delta-valerolactone) and poly(gamma-butyrolactone), for example,are also useful. The biodegradable regions may have a degree ofpolymerization ranging from one up to values that would yield a productthat was not substantially water soluble. Thus, monomeric, dimeric,trimeric, oligomeric, and polymeric regions may be used.

[0076] Biodegradable regions can be constructed from polymers ormonomers using linkages susceptible to biodegradation, such as ester,peptide, anhydride, orthoester, phosphazine and phosphoester bonds. Thetime required for a polymer to degrade can be tailored by selectingappropriate monomers. Differences in crystallinity also alterdegradation rates. For relatively crystalline or hydrophobic polymers,actual mass loss may only begin when the oligomeric fragments are smallenough to be water soluble. Thus, initial polymer molecular weight andstructure will influence the degradation rate.

[0077] INITIATORS

[0078] The term “initiator” is used herein in a broad sense, in that itis a composition which under appropriate conditions will result in thepolymerization of a monomer. Materials for initiation may bephotoinitiators, chemical initiators, thermal initiators,photosensitizers, co-catalysts, chain transfer agents, and radicaltransfer agents. All initiators known in the art are potentiallysuitable for the practice of the priming technique. The criticalproperty of an initiator is that the polymerization will not proceed ata useful rate without the presence of the initiator.

[0079] The “priming” initiator must adhere sufficiently to the surfaceto be coated to provide a local source of initiation of the reactionwith the particular monomers to be applied. The initiator must also notbe toxic when used in biologically-related applications, at least in theamounts applied. The initiator is preferably a photoinitiator. Indiscussing photoinitiators, a distinction may be drawn betweenphotosensitizers and photoinitiators—the former absorb radiationefficiently, but do not initiate polymerization well unless theexcitation is transferred to an effective initiator or carrier.Photoinitiators as referred to herein include both photosensitizers andphotoinitiators, unless otherwise noted.

[0080] Photoinitiators provide important curing mechanisms for additionpolymerization, and especially for curing of ethylenically-unsaturatedcompounds, such as vinylic and acrylic-based monomers. Any of thephotoinitiators found in the art may be suitable, if they adhere to theparticular surface. Examples of photo-oxidizable and photo-reducibledyes that may be used to initiate polymerization include acridine dyes,for example, acriblarine; thiazine dyes, for example, thionine; xanthinedyes, for example, rose Bengal; and phenazine dyes, for example,methylene blue. Other initiators include camphorquinones andacetophenone derivatives. Photoinitiation is a preferred method ofpolymerizing the coatings and adhesives.

[0081] The choice of the photoinitiator is largely dependent on thephotopolymerizable regions. For example, when the macromer includes atleast one carbon-carbon double bond, light absorption by the dye causesthe dye to assume a triplet state, the triplet state subsequentlyreacting with the amine to form a free radical which initiatespolymerization. In an alternative mechanism, the initiator splits intoradical-bearing fragments which initiate the reaction. Preferred dyesfor use with these materials include eosin dye and initiators such as2,2-dimethyl-2-phenylacetophenone, 2-methoxy-2-phenylacetophenone,Darocur™ 2959, Irgacure™ 651 and camphorquinone. Using such initiators,copolymers may be polymerized in situ by long wavelength ultravioletlight or by light of about 514 nm, for example.

[0082] A preferred photoinitiator for biological use is Eosin Y, whichabsorbs strongly to most tissue and is an efficient photoinitiator.

[0083] It is known in the art of photopolymerization to use a wavelengthof light which is appropriate for the activation of a particularinitiator. Light sources of particular wavelengths or bands arewell-known.

[0084] Thermal polymerization initiator systems may also be used.Systems that are unstable at 37° C. and initiate free radicalpolymerization at physiological temperatures include, for example,potassium persulfate, with or without tetramethyl ethylenediamine;benzoyl peroxide, with or without triethanolamine; and ammoniumpersulfate with sodium bisulfite. Other peroxygen compounds includet-butyl peroxide, hydrogen peroxide and cumene peroxide. As describedbelow, it is possible to markedly accelerate the rate of a redoxpolymerization by including metal ions in the solution, especiallytransition metal ions such as the ferrous ion. It is further shownbelow, that a catalysed redox reaction can be prepared so that theredox-catalysed polymerization is very slow, but can be speeded updramatically by stimulation of a photoinitiator present in the solution.

[0085] A further class of initiators is provided by compounds sensitiveto water, which form radicals in its presence. An example of such amaterial is tri-n-butyl borane, the use of which is described below.

[0086] REDOX INITIATORS

[0087] Metal ions can be either an oxidizer or a reductant in systemsincluding redox initiators. For example, in some examples below, ferrousion is used in combination with a peroxide to initiate polymerization,or as parts of a polymerization system. In this case the ferrous ion isserving as reductant. Other systems are known in which a metal ion actsas oxidant. For example, the ceric ion (4+ valence state of cerium) caninteract with various organic groups, including carboxylic acids andurethanes, to remove an electron to the metal ion, and leaving aninitiating radical behind on the organic group. Here the metal ion actsas an oxidizer. Potentially suitable metal ions for either role are anyof the transition metal ions, lanthanides and actinides, which have atleast two readily accessible oxidation states. Preferred metal ions haveat least two states separated by only one difference in charge. Ofthese, the most commonly used are ferric/ferrous; cupric/cuprous;ceric/cerous; cobaltic/cobaltous; vanadate V vs. IV; permanganate; andmanganic/manganous.

[0088] CO-INITIATORS AND COMONOMERS

[0089] Any of the compounds typically used in the art as radicalgenerators or co-initiators in photoinitiation may be used. Theseinclude co-catalysts or co-initiators such as amines, for example,triethanolamine, as well as other trialkyl amines and trialkylol amines;sulfur compounds; heterocycles, for example, imidazole; enolates;organometallics; and other compounds, such as N-phenyl glycine.

[0090] Co-monomers can also be used. They are especially useful when themonomer is a macromolecule, as in Example 1 below; in that case, any ofthe smaller acrylate, vinyl or allyl compounds can be used. Comonomerscan also act as accelerators of the reaction, by their greater mobility,or by stabilizing radicals. Of particular interest are N-vinylcompounds, including N-vinyl pyrrolidone, N-vinyl acetamide, N-vinylimidazole, N-vinyl caprolactam, and N-vinyl formamide.

[0091] SURFACTANTS, STABILIZER, AND PLASTICIZERS

[0092] Other compounds can be added to the initiator and/or monomersolutions. Surfactants may be included to stabilize any of thematerials, either during storage or in a form reconstituted forapplication. Similarly, stabilizers which prevent prematurepolymerization may be included; typically, these are quinones,hydroquinones, or hindered phenols. Plasticizers may be included tocontrol the mechanical properties of the final coatings. These are alsowell-known in the art, and include small molecules such as glycols andglycerol, and macromolecules such as polyethylene glycol.

[0093] SURFACES TO BE TREATED

[0094] Surfaces to be coated include biologically-related surfaces ofall kinds, and include the surface of drug delivery devices such ascatheters or prosthetic implants. Any tissue or cell surface iscontemplated, as well as the surface of a device to be used in the bodyor in contact with bodily fluids. A coating may be applied to thesurface of any of these, in an amount effective to improve tenacity ofadherence. Moreover, the technique may be used to adhere surfaces toeach other. For example, wounds in living tissue may be bonded or sealedusing this technique or preformed medical appliances may be bonded totissue. Examples of such applications are grafts, such as vasculargrafts; implants, such as heart valves, pacemakers, artificial corneas,and bone reinforcements; supporting materials, such as meshes used toseal or reconstruct openings; and other tissue-non-tissue interfaces. Aparticularly important class of tissue surfaces is those which arefriable, and therefore will not support sutures well. Adherent coatingscan seal the suture lines, support sutured areas against mechanicalstress, or substitute entirely for sutures when mechanical stress islow. Examples of such situations include vascular anastomosis, nerverepair, repair of the cornea or the cochlea, and repair of the lung,liver, kidney and spleen.

[0095] The priming technique can also be used on non-tissue surfaces ingeneral, where useful bonds may be formed between similar or dissimilarsubstances, and solid or gel coatings are tightly adhered to surfaces.In particular, a pre-formed gel, or other fragile material, may betightly adhered to a supporting material by this method.

[0096] The priming method is advantageous because it can be used to coatand or to bond together any of a wide variety of surfaces. These includeall surfaces of the living body, and surfaces of medical devices,implants, wound dressings and other body-contacting atrificial ornatural surfaces. These include, but are not limited to, at least onesurface selected from the following: a surface of the respiratory tract,the meninges, the synovial spaces of the body, the peritoneum, thepericardium, the synovia of the tendons and joints, the renal capsuleand other serosae, the dermis and epidermis, the site of an anastomosis,a suture, a staple, a puncture, an incision, a laceration, or anapposition of tissue, a ureter or urethra, a bowel, the esophagus, thepatella, a tendon or ligament, bone or cartilage, the stomach, the bileduct, the bladder, arteries and veins; and devices such as percutaneouscatheters (e.g. central venous catheters), percutaneous cannulae (e.g.for ventricular assist devices), urinary catheters, percutaneouselectrical wires, ostomy appliances, electrodes (surface and implanted),and implants including pacemakers, defibrillators, and tissueaugmentations.

[0097] BIOLOGICALLY ACTIVE AGENTS

[0098] Biologically active materials may be included in any of thecoatings described herein, as ancillaries to a medical treatment (forexample, antibiotics) or as the primary objective of a treatment (forexample, a gene to be locally delivered). A variety of biologicallyactive materials may be included, including passively-functioningmaterials such as hyaluronic acid, as well as active agents such asgrowth hormones. All of the common chemical classes of such agents areincluded: proteins (including enzymes, growth factors, hormones andantibodies), peptides, organic synthetic molecules, inorganic compounds,natural extracts, nucleic acids (including genes, antisense nucleotides,ribozymes and triplex forming agents), lipids and steroids,carbohydrates (including heparin), glycoproteins, and combinationsthereof.

[0099] The agents to be incorporated can have a variety of biologicalactivities, such as vasoactive agents, neuroactive agents, hormones,anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics,antivirals, or may have specific binding properties such as antisensenucleic acids, antigens, antibodies, antibody fragments or a receptor.Proteins including antibodies or antigens can also be delivered.Proteins are defined as consisting of 100 amino acid residues or more;peptides are less than 100 amino acid residues. Unless otherwise stated,the term protein refers to both proteins and peptides. Examples includeinsulin and other hormones.

[0100] Specific materials include antibiotics, antivirals,antiinflammatories, both steroidal and non-steroidal, antineoplastics,anti-spasmodics including channel blockers, modulators ofcell-extracellular matrix interactions including cell growth inhibitorsand anti-adhesion molecules, enzymes and enzyme inhibitors,anticoagulants and/or antithrombotic agents, growth factors, DNA, RNA,inhibitors of DNA, RNA or protein synthesis, compounds modulating cellmigration, proliferation and/or growth, vasodilating agents, and otherdrugs commonly used for the treatment of injury to tissue. Specificexamples of these compounds include angiotensin converting enzymeinhibitors, prostacyclin, heparin, salicylates, nitrates, calciumchannel blocking drugs, streptokinase, urokinase, tissue plasminogenactivator (TPA) and anisoylated plasminogen activator (TPA) andanisoylated plasminogen-streptokinase activator complex (APSAC),colchicine and alkylating agents, and aptomers. Specific examples ofmodulators of cell interactions include interleukins, platelet derivedgrowth factor, acidic and basic fibroblast growth factor (FGF),transformation growth factor β (TGF β), epidermal growth factor (EGF),insulin-like growth factor, and antibodies thereto. Specific examples ofnucleic acids include genes and cDNAs encoding proteins, expressionvectors, antisense and other oligonucleotides such as ribozymes whichcan be used to regulate or prevent gene expression. Specific examples ofother bioactive agents include modified extracellular matrix componentsor their receptors, and lipid and cholesterol sequestrants.

[0101] Examples of proteins further include cytokines such asinterferons and interleukins, poetins, and colony-stimulating factors.Carbohydrates include Sialyl Lewis^(x) which has been shown to bind toreceptors for selectins to inhibit inflammation. A “Deliverable growthfactor equivalent” (abbreviated DGFE), a growth factor for a cell ortissue, may be used, which is broadly construed as including growthfactors, cytokines, interferons, interleukins, proteins,colony-stimulating factors, gibberellins, auxins, and vitamins; furtherincluding peptide fragments or other active fragments of the above; andfurther including vectors, i.e., nucleic acid constructs capable ofsynthesizing such factors in the target cells, whether by transformationor transient expression; and further including effectors which stimulateor depress the synthesis of such factors in the tissue, includingnatural signal molecules, antisense and triplex nucleic acids, and thelike. Exemplary DGFE's are vascular endothelial growth factor (VEGF),endothelial cell growth factor (ECGF), basic fibroblast growth factor(bFGF), bone morphogenetic protein (BMP), and platelet derived growthfactor (PDGF), and DNA's encoding for them Exemplary clot dissolvingagents are tissue plasminogen activator, streptokinase, urokinase andheparin.

[0102] Drugs having antioxidant activity (i.e., destroying or preventingformation of active oxygen) may be used, which are useful, for example,in the prevention of adhesions. Examples include superoxide dismutase,or other protein drugs include catalases, peroxidases and generaloxidases or oxidative enzymes such as cytochrome P450, glutathioneperoxidase, and other native or denatured hemoproteins.

[0103] Mammalian stress response proteins or heat shock proteins, suchas heat shock protein 70 (hsp 70) and hsp 90, or those stimuli which actto inhibit or reduce stress response proteins or heat shock proteinexpression, for example, flavonoids, also may be used.

[0104] The macromers may be provided in pharmaceutical acceptablecarriers known to those skilled in the art, such as saline or phosphatebuffered saline. For example, suitable carriers for parenteraladministration may be used.

[0105] Methods of Treatment

[0106] Generally, any medical condition which requires a coating orsealing layer may be treated by the methods described herein to producea coating with better adherence. For example, lung tissue may be sealedagainst air leakage after surgery using the priming technique. Likewise,wounds may be closed; leakage of blood, serum, urine, cerebrospinalfluid, air, mucus, tears, bowel contents or other bodily fluids may bestopped or minimized; barriers may be applied to prevent post-surgicaladhesions, including those of the pelvis and abdomen, pericardium,spinal cord and dura, tendon and tendon sheath. The technique may alsobe useful for treating exposed skin, in the repair or healing ofincisions, abrasions, burns, inflammation, and other conditionsrequiring application of a coating to the outer surfaces of the body.The technique is also useful for applying coatings to other bodysurfaces, such as the interior or exterior of hollow organs, includingblood vessels. In particular, restenosis of blood vessels or otherpassages can be treated. The techniques can also be used for attachingcell-containing matrices, or cells, to tissues, such as meniscus orcartilage.

[0107] GENERAL SEALING OF BIOLOGICAL TISSUES

[0108] As shown in the examples below, the priming method ofpolymerization is especially effective in the sealing of biologicaltissues to prevent leakage. However, the examples also demonstrate thata degree of sealing can be achieved with photopolymerizable systemswithout the improvement of priming the tissue with photopolymerizinginitiator. There have been numerous attempts to reliably seal tissuewith a number of materials, including most prominently cyanoacrylatesand fibrin glues. None of these prior art techniques has been entirelysatisfactory. Cyanoacrylates, which polymerize on exposure to moisture,and can be accelerated by amines, are very “stiff” once polymerized. Ifthere is any motion of the biological material, they tend to crack, andlose their self-cohesion and/or their adherence to tissue. Fibrin gluescan be difficult to prepare, especially in the currently-preferredautologous version; they require enzymatic or toxic chemical means to begelled or crosslinked; and they are rapidly degraded by native enzymes.

[0109] The range of uses of sealing or bonding materials in the body isvery large, and encompasses many millions of potential uses each year.In cardiovascular surgery, uses for tissue sealants include bleedingfrom a vascular suture line; support of vascular graft attachment;enhancing preclotting of porous vascular grafts; stanching of diffusenonspecific bleeding; anastomoses of cardiac arteries, especially inbypass surgery; support of heart valve replacement; sealing of patchesto correct septal defects; bleeding after sternotomy; and arterialplugging. Collectively, these procedures are performed at a rate of 1 to2 million annually.

[0110] In other thoracic surgery, uses include sealing of bronchopleuralfistulas, reduction of mediastinal bleeding, sealing of esophagealanastomoses, and sealing of pulmonary staple or suture lines. Inneurosurgery, uses include dural repairs, microvascular surgery, andperipheral nerve repair. In general surgery, uses include bowelanastomoses, liver resection, biliary duct repair, pancreatic surgery,lymph node resection, reduction of seroma and hematoma formation,endoscopy-induced bleeding, plugging or sealing of trocar incisions, andrepair in general trauma, especially in emergency procedures.

[0111] In plastic surgery, uses include skin grafts, burns, debridementof eschars, and blepharoplasties (eyelid repair). In otorhinolaryngology(ENT), uses include nasal packing, ossicular chain reconstruction, vocalcord reconstruction and nasal repair. In opthalmology, uses includecorneal laceration or ulceration, and retinal detachment. In orthopedicsurgery, uses include tendon repair, bone repair, including filling ofdefects, and meniscus repairs. In gynecology/obstetrics, uses includetreatment of myotomies, repair following adhesiolysis, and prevention ofadhesions. In urology, sealing and repair of damaged ducts, andtreatment after partial nephrectomy are potential uses. Sealing can alsobe of use in stopping diffuse bleeding in any of a variety ofsituations, including especially treatment of hemophiliacs. In dentalsurgery, uses include treatment of periodontal disease and repair aftertooth extraction. Repair of incisions made for laparoscopy or otherendoscopic procedures, and of other openings made for surgical purposes,are other uses. Additional uses include separation of tissues to preventdamage by rugging during healing. Similar uses can be made in veterinaryprocedures. In each case, appropriate biologically active components maybe included in the sealing or bonding materials.

[0112] APPLICATION TECHNIQUES AND DEVICES

[0113] Both priming and polymer addition may be accomplished by simpledripping of material onto the surface to be coated. This can beaccomplished using common devices such as a syringe, a pipet, or a hose,depending on scale. More uniform applications may be obtained using anapplicator, such as a brush, a pad, a sponge, a cloth, or a spreadingdevice such as a finger, a coating blade, a balloon, or a skimmingdevice. These may further be used to rub the surface to improvepenetration of the primer or the monomer, or to mix primer and monomerin situ on the surface. In large-scale applications, fluid layers may beapplied with large-scale coating machinery, including roll coaters,curtain coaters, gravure and reverse gravure devices, and any of thecoating devices known in the art. Sprayers may be used at any scale,especially for lower-viscosity primers or polymerizable monomer layers.

[0114] Application techniques and devices may be combined, as inapplying fluid from a syringe, and then rubbing it into the surface witha finger tip. Such operations may be repeated, as in applying drops ofpriming initiator; rubbing these into the surface with a brush;repeating this operation; adding monomer solution; rubbing it in; andfinally applying additional layers of monomer before or during theapplication of curing means, such as light, heat, or slow release ofperoxide radicals.

[0115] An additional application means which is required in many coatingtechniques described herein, and in particular in the preferred coatingmethod which uses photoinitiation to cure the monomer, is a lightsource. For large-scale application, flood lamps and similar devices areuseful. In small, localized applications, such as tissue sealing andcoating, it may be preferable to use a localized source such as a fiberoptic or light guide, which can project radiation of the appropriatewavelength onto the site to be treated to cause polymerization of themonomer. Also, a light emitter could be carried on a device, as aminiature bulb. A focused beam from a remote source could be suitableif, for example, the surface was exposed. In exposed surfaces, it ispossible that ambient light could be sufficient to polymerize thecoating, especially at high initiator levels.

[0116] Each of the applications means can be separate, so that a kit ofapplication means could contain, for example, one or more containers orreservoirs, one or more pads or brushes, and if required at least onelight guide. The application means could also be combined in whole or inpart. For example, a dripping device, such as a tube, could be combinedwith a spreading device, such as a brush. These could further becombined with a light guide. Such combination devices are especiallydesirable in treatment of living organisms, and especially humans, tomaximize the simplicity of a procedure and the probability of correctlyconducting it.

[0117] COMPLIANCE PROPERTIES

[0118] The compliance properties of the material herein described arethose of the material after it has polymerized to form a polymerizedmaterial. As used herein, “polymerized material” includes material whichforms by the ionic or covalent reaction of monomer precursor molecules.Preferably, the polymerized material is formed by covalent reactions ofthe monomers. It can be very difficult to measure the elastic propertiesof the material when adhered to tissue. The mechanical properties aretherefore when appropriate measured on samples made in vitro, either ina mold, or, as in the lap-shear test, in contact with standardizedtissue. Such measurements must be corrected to conditions applicable totissue treatment, including the diluting effects of polymerizationreagents, or of fluids on the tissue. Thus, a sealing solution may beapplied to tissue at a concentration of 30%, but in the coating processit may be diluted to 15% effective concentration by dilution with bloodor plasma. Similarly, especially in the case of fibrin sealant, thepolymer concentration may be reduced by mixing with polymerizingreagents, either in bulk or by spraying. Where appropriate, suchcorrections have been taken into account in the descriptions herein.Materials may be equilibrated with water before testing either byabsorption or syneresis.

[0119] In light of these observations, an effective material for forminga compliant coating or sealant preferably has a strain or elongationbefore fracture substantially similar to or at least as great as theexpected strain during normal use of the tissue to which it is applied,and the elongation of the polymerized material is preferably reversible.This is to avoid either detachment from the tissue or fracture, orlimitation of the tissue's natural expansion. Preferably, the effectivecompliant material will have a reversible elongation at least about 150%as great, more preferably at least about 200% as great, and still morepreferably at least about 300% as great as the expected strain of thetissue.

[0120] The polymerized material thus may be designed and selected forapplication to different tissue, to have an elongation at rupture whichis similar to or greater than the elongation of the tissue in vivoduring its function. The elongation at rupture of the polymerizedmaterial can be, for example, greater than 100% or 200%, or optionallygreater than 300% or 400%. In some embodiments, the elongation atrupture of the polymerized material may be between for example 100% and700%, depending on the tissue properties. In some applications, anelongation at rupture greater than 700% is useful.

[0121] In addition, the compliant material, for example in sealantapplications, preferably should have a normalized compliance that iscomparable in magnitude to the normalized compliance of the tissue towhich it is applied. The material will be operative even when thematerial's normalized compliance is much greater than the normalizedcompliance of the tissue.

[0122] In cases where minimal modification of the natural expansion andcontraction of a tissue is desired, the preferred range of thenormalized compliance ratio extends from about 0.05 to about 3,preferably from about 0.1 to about 2.0, and more preferably from about0.1 to about 1.0. In some cases, for example when the tissue is lungtissue, a value of the elastic modulus of less than about 150 kPa,preferably less than 100 kPa, more preferably less than about 50 kPa,and most preferably less than about 30 kPa is preferred.

[0123] To obtain the desired ratio of the normalized compliance of thepolymerized material to the normalized compliance of tissue, the overallforce required to stretch the sealant layer should be adjusted, sincethat of the tissue is fixed. The adjustment can be accomplished by anyof several known methods, including the alteration of the thickness ofthe layer of the polymerized material, or the variation of the polymerconcentration, or of the polymer crosslink density, or of otherproperties of the material. The properties of the precursor materialsand the reaction conditions may be adjusted to produce desired otherproperties of the polymerized material, such as sealant or adhesiveproperties, or controlled degradation and drug release properties

[0124] Where prevention of tissue deformation is desired, for exampleduring a healing period, the parameters of the tissue coating can beadjusted so that the normalized compliance ratio is significantly inexcess of 1.

[0125] The adherence of the polymerized material to the tissue isimportant in order to obtain the benefits of proper complianceproperties. An adherence of at least about 20 gm/cm² in a single ordouble lap shear test is preferable for many applications. Use ofpriming technology, described elsewhere in this application, is aneffective method for obtaining such values. In some applications, suchas the use of the polymerized material as a tissue sealant, adherencevalues of about 30 gm/cm² are preferred, and values at or above 40gm/cm² are more preferred.

[0126] In many applications, such as tissue sealing, the viscosity ofthe precursor materials can be tailored to obtain optimal coatings.Higher viscosities can favor retention of the uncured or unpolymerizedsealant at the site of application, and minimize displacement of thesealant by the presence of bodily fluids at the surface. However, higherviscosities make the material more difficult to apply. A suitable rangeof viscosity, for example, for the sealant portion of a sealing systemis in the range of about 200 cP (centipoise) to about 40,000, preferablyabout 500 to about 5000 cP, and more preferably about 700 to about 1200cP For lung, a suitable range of viscosity is about 900 to 1000 cP. Theoptimal viscosity will depend on the site of application and the natureof the condition which is to be alleviated by the application of thematerial

[0127] PACKAGING

[0128] The materials for making the coating can be packaged in anyconvenient way, and may form a kit including for example separatecontainers, alone or together with the application device. The reactivemonomers are preferably stored separately from the initiator, unlessthey are co-lyophilized and stored in the dark, or otherwise maintainedunreactive. A convenient way to package the materials is in three vials(or prefilled syringes), one of which contains concentrated initiatorfor priming, the second of which contains reconstitution fluid, and thethird containing dry or lyophilized monomer. Dilute initiator is in thereconstitution fluid; stabilizers are in the monomer vial; and otheringredients may be in either vial, depending on chemical compatibility.If a drug is to be delivered in the coating, it may be in any of thevials, or in a separate container, depending on its stability andstorage requirements.

[0129] It is also possible, for a more “manual” system, to package someor all of the chemical ingredients in pressurized spray cans for rapiddelivery. If the monomer is of low enough viscosity, it can be deliveredby this route. A kit might then contain a spray can of initiator; aspray can or dropper bottle of monomer, initiator and other ingredients;and an optional spreading or rubbing device. If the monomer andinitiator system are designed to polymerize under the influence ofnatural or operating room light, possibly with the supplement of achemical initiator or carrier such as a peroxygen compound, then thetechnique could be suitable for field hospital or veterinary situations.

[0130] The present invention will be further understood by reference tothe following non-limiting examples.

EXAMPLE 1

[0131] Relative adhesion of coating to primed and unprimed surfaces.

[0132] Fresh pig lung was primed in one area with a solution ofphotoinitiator (Eosin Y, 1 mg/mL (1000 ppm) in normal saline) and inanother area with normal saline (prior art control). Excess fluid wasremoved by blotting. About 0.5 mL of monomer solution was applied toeach spot. The monomer was polyethylene glycol (35,000 Daltons)terminated with caprolactone (average of 3.3 caprolactone groups perpolyethylene glycol molecule) and capped with acrylic acid, essentiallyas described in Hubbell et al. The monomer solution contained 15%monomer (w/w), 90 mM triethanolamine, 20 ppm (w/w) Eosin Y, and 5microliters/mL vinylpyrrolidone (v/v). The samples were irradiated withgreen light until cured (40 sec. at 100 mW/cm²) into a firm, transparentgel. Initial adherence was seen in both primed and control spots,although the primed spots had better overall adherence.

[0133] The lung was connected to a pressure-controlled inflationapparatus, and subjected to chronic fatigue for 1 hour of pneumaticinflation pressures at 25 to 30 cm of water, in 6 second cycles. Thiswas designed to simulate the effects of breathing. After the fatiguetest, the primed gel spots were still adherent, but the control gelspots could easily be lifted from the lung surface with forceps. Thus,adhesion under chronic stress was better with priming beforepolymerization.

EXAMPLE 2

[0134] Sealing of wedge resection of lung.

[0135] In lung operations, it is common to make a “wedge resection” toremove diseased areas. A combination stapler/cutter is used tosimultaneously cut and staple along one side of the wedge to be removed,and is then used to staple and cut the other side so that a wedge-shapedpiece of lung is removed, while the remaining lung is simultaneouslystapled closed. Despite a high staple density, the staple lines areprone to leak air, which can produce severe complications in a patientundergoing such an operation.

[0136] Frozen-thawed pig lungs were wedge-resectioned, using aProxiMate™ TLC 55 reloadable linear cutter/stapler (Ethicon; Somerville,N.J.). Every second staple was omitted from the outer staple lines inthe cassette to reliably induce leaks. Lungs were inflated with air to apressure of 40 cm H₂O, and leaks were observed by pushing the stapledarea just under the surface of a water bath (similar to leak testing ofan inner tube). Next, staple lines were primed with 1000 ppm Eosin Y,blotted, and treated with the macromer mixture of Example 1 which wasthen cured as described.

[0137] In a standard test for durability, the lungs were inflated to 20cm water pressure for 10 cycles, over a period of 1 minute, and thenheld for 30 seconds at 40 cm water. The primed and sealed lung sectionsshowed no leaks, demonstrating the effectiveness of the priming systemin sealing known leaks.

[0138] Finally, pressure was increased in the primed lungs to determinethe maximum pressure before leakage. Small leaks were typically seen at75 cm water or above.

EXAMPLE 3

[0139] Lap/Shear Strength of Primed and Unprimed Bonds.

[0140] Adhesion under shear of gel to rat skin was determined on anInstron™ apparatus using standard methods. The biological surface wasrat back skin, freshly removed from euthanized animals. It was glued toa glass slide, and treated as described below. A casting chamber waspositioned above the skin, which also contained a gauze mesh whichprotruded from the chamber. Monomer solution was injected into thechamber and polymerized. The chamber was removed, and the tensilestrength of the bond was determined by shearing the lap between theglass slide and the gauze mesh in a standard load cell on the Instron™.

[0141] Skin treatments included none (control); primed; primed andpre-coated with monomer solution by drip; and primed, pre-coated withmonomer solution by drip, and rubbed or mixed with a brush. A monomersolution as in Example 1 was applied, except that the monomer, “8KL5”,had a smaller PEG molecule (8000 D), and was extended with lactategroups rather than caprolactone groups. With unprimed skin, a differentinitiator, Irgacure™ 651 (Ciba Geigy), was also used in the gellingmonomer mixture.

[0142] With the non-primed Irgacure™ system, average load at failure for6 to 8 samples ranged from 49 grams of force with low-intensity mixingof monomer onto the surface, to 84 to 274 g. with rubbing. Similarresults were obtained with the Eosin catalysed system with no primer(146 g average, range 80-220) When the tissue was pre-primed with Eosin,and monomer solution was thoroughly mixed with a brush, the failureforce increased to 325 g (range 220-420). Thus priming canquantitatively improve early adherence, in addition to its much largerimprovement in adherence after flexing.

EXAMPLE 4

[0143] Sealing of a bronchus.

[0144] A bronchus was stapled and cut during lobectomy by the techniquesdescribed for wedge resectioning. The staple line was coated asdescribed in Example 2, likewise preventing or stopping air leaks.

EXAMPLE 5 Sealing of a laceration

[0145] A laceration 2 mm deep by 2 cm long was made on an isolated lungwith a scalpel; the scalpel was taped to control the depth of cut. Thelung was tested and found to leak. The laceration was primed, filledwith monomer solution containing initiator, and the monomer wasphotopolymerized. The leak was sealed by this procedure.

EXAMPLE 6

[0146] Coating of a medical device.

[0147] A length of polyurethane tubing extrusion used for cathetershafts was dipped into an aqueous solution containing 20 ppm eosin.Excess eosin was rinsed off with water. The primed tubing was dippedinto a solution containing 10% monomer (type 8KL5, as in example 3), 90mM triethanolamine, 5 ppm vinylpyrrolidone, and 20 ppm eosin. Excessmonomer was allowed to drip off. The monomer layer on the tubing wasthen photopolymerized to form an adherent gel coating. The adherence wasstrong enough to survive sectioning of the tubing with a razor blade;photomicrography showed complete adherence of the gel to the tubing. Asa prior art control, the shaft was not primed. After dipping theun-primed shaft into the same monomer solution, the coating on the shaftwas photopolymerized. A gel was formed, but failed to adhere to theshaft, and fell off during handling.

EXAMPLE 7

[0148] Priming for surface adherence

[0149] Two surfaces of Pebax™ polyeteramid were stained with 1000 ppmEosin Y and rinsed. Polymerizable monomer solution (10% 8KLS in watercontaining 20 ppm eosin) was placed between the surfaces, and thesandwich was exposed to green light. Gel formed in the interface andheld the surfaces together. In a control experiment, in which thesurfaces were not primed, polymerization of the monomer occurred but nosignificant adherence of the surfaces was found.

EXAMPLE 8 Priming of surfaces.

[0150] On exposure to 1000 ppm of Eosin Y, surfaces of Teflon™fluoropolymer and of polyethylene were observed to stain significantly.When monomer was added to such surfaces, and allowed to stand briefly,gels were formed on illumination. Adherence seemed inferior to thatobtained on polyurethane.

EXAMPLE 9

[0151] Priming of Uterine Horn and Adherence of Gel Layers.

[0152] A model system was established for placing of barriers onmammalian uteruses after operations. Freshly excised uterine horns fromeuthanized pigs were removed from a saline bath and treated with 1000ppm Eosin. Controls were not primed. Polymerizable monomer solution asin Example 7 was applied to the primed and control areas. Adherence ofgel layers to the primed areas was very firm, while gels on controlareas could be dislodged.

EXAMPLE 10

[0153] Water-sensitive initiation.

[0154] It is known to use tributylborane as a water-sensitive initiatorof bulk polymerization. In this example, it is shown that TBB can serveas an initiator in interfacial polymerization, and thus as a primer.

[0155] 1 M tributylborane (TBB) solution in THF was purchased fromAldrich. Lyophilized 35KL4A2 reactive monomer containing triethanolamine and eosin was made in these laboratories. Polyethylene glycol 400(PEG 400) was obtained from Union Carbide). Of the lyophilized powder of35KL4A2, 0.5 gram was dissolved in 9.5 grams of PEG 400. The mixture waswarmed using a heat gun up to 40-50°C. to facilitate dissolution. Tothis solution, 30 μL of vinyl pyrrolidinone were added as a comonomer.

[0156] Using a glass syringe, 2 ml TBB solution were transferred to asprayer, of the type used with thin layer chromatography plates. A smallamount of TBB solution was sprayed on a glass coverslip and the PEG 400solution containing 3SKL4A2 was applied on the TBB solution. Animmediate polymerization of the solution was noticed. The polymerizedfilm was insoluble in water indicating crosslinking.

[0157] Similar polymerization was carried out on pig lung tissue. Asmall amount of TBB solution was sprayed on approximately 3 cm² of lungtissue. A 35KL4A2 solution in PEG was applied on top of the TBBsolution. A small amount of TBB solution was also sprayed on top of themonomer solution. A well adherent film of 35KL4A2 on lung tissue wasnoticed. The polymerized film was elastic and well adherent to thetissue.

[0158] In an alternative procedure, application of the TBB initiator totissue may be followed by application of monomer solution containing aphotoinitiator, such as 20 ppm eosin. Photopolymerization is then usedto build a thick layer of gel onto the initiated priming layer. Goodadherence is predicted.

EXAMPLE 11

[0159] Combination of redox free radical initiation systems withphotoinitiation and/or thermal free radical initiation systems forincreased polymerization speed.

[0160] Previous visible light photopolymerization of Focal macromonomersuses the aqueous eosin Y/triethanolamine photoinitiation system. Thisreaction has been observed to generate peroxides when carried out in thepresence of dissolved oxygen in the buffer. One may exploit thesegenerated peroxides as an additional source of free radical initiatorsfor polymerization using a Fenton-Haber-Weiss style reaction. In aneffort to use these formed peroxides as polymerization initiators,ferrous ion in the form of ferrous sulfate was added to the eosinY/triethanolamine buffer and used in the photopolymerization of Focalmacromonomers. Using an indentation style hardness test, gel stiffnessas a function of illumination time was used as a measure of gel cure.

[0161] In an experiment to evaluate the effectiveness of 50 ppm ferrousion on the gelation of the Focal macromonomer 8KL5, two buffers wereprepared. The first buffer was prepared in deionized (DI) water using90.4 mM triethanolamine(TEOA) and pH adjusting to 7.4 with 6 N HCl. Thesecond buffer was prepared similarly but with the addition of ferroussulfate such that there would be approximately 50 ppm ferrous ionavailable. These buffers were used to prepare a 10% (w/v) 8KL5 gellingsolution with 1 microliter of vinyl pyrrolidinone per ml of gellingsolution added as a comonomer. These solutions were then divided intogelling samples and had 20 ppm of eosin Y added to them. These sampleswere then illuminated using an all lines Ar laser at a power of 100mW/cm². All illumination timepoints were done in triplicate and keptdark until stiffness testing was performed. In comparing a 10% (w/v)Focal macromonomer gelling solution with and without 50 ppm of ferrousion added, the gel with the added iron gave significantly more curedgels than did the gel without iron.

[0162] It is further believed that any free radical initiation system,especially aqueous ones, capable of generating soluble peroxides can begreatly enhanced by the addition of soluble metal ions capable ofinducing the decomposition of the formed peroxides.

EXAMPLE 12

[0163] Redox-accelerated curing (“dual cure”) of primed systems.

[0164] A redox-accelerated system was compared to a purelyphotoinitiated system for priming tissues. The accelerated system wasfound to be especially effective in the presence of blood, whichattenuates the light used in photopolymerization. An acute rabbit lungmodel of sealing of air leaks was used. A thoracotomy was made underanesthesia in the intercostal space of the rabbit Anesthesia was inducedusing an intramuscular injection of ketamine-acepromazine. The seventhrib was removed to facilitate access to the lungs, and the animal wasmaintained on assisted ventilation. A laceration, about 8 mm×2 mm, wasmade on each of the middle and lower lobes of the lung. Air and bloodleaks were immediately apparent. Bleeding was tamponaded using a gauzesponge, and the site was then rinsed with saline. Some blood remained,and a slow ooze of blood and air leakage from the site was stillpersistent on ventilation.

[0165] Two formulations were compared. In the first formulation, thepriming solution contained 500 ppm Eosin Y and 90 mM TEOA(triethanolamine) in WFI (water for injection), while the macromersolution contained 15% w/v macromer (type 35KL4), 20 ppm Eosin Y, 5mg/ml vinylcaprolactam, and 90 mM TEOA in WFI.

[0166] The second formulation contained 500 ppm Bosin Y, 15% 35KL4, and3 mg/ml ferrous gluconate in WFI in the primer, and the same macromersolution as in the first formulation, supplemented with 500 ppm t-butylperoxide.

[0167] Application methods were the same for both formulations, andconsisted of application of 1 ml primer with gentle brushing, followedby application of 0.5 ml macromer solution by brushing, and thenillumination with blue-green light at 100 mW/(square centimeter) whiledripping an additional 0.5 ml of macromer. Total illumination time was40 sec. Gels were formed on the tissue by both treatments, and the airand blood leakages were sealed.

[0168] Acute adhesion of the gel to tissue was rated on a scale of 1(poor) to 4 (excellent). The first formulation scored 1.5, and thesecond scored 3.5. A notable improvement in adherence of the gel to theliving lungs was seen with the use of the dual cure system.

EXAMPLE 13

[0169] Optimization of iron concentrations.

[0170] The objective is to find a redox system which does notinstantaneously gel the macromer, and which can also be cured by light.Various formulae were prepared, and their polymerization was studied.

[0171] A stock monomer solution (solution 1) contained 15% w/wu35KL4macromer, lot 031395AL, in TEOA buffer (90 mM triethanolamine,neutralized to pH 7.4 with HCl, in water for injection), and 4000 ppm VC(vinylcaprolactam) and 20 ppm eosin Y (photoinitiator). The buffer wasselected to be compatible with dissolved iron.

[0172] Iron-monomer solution (solution 2) contained in addition 20 mg/mlof ferrous gluconate, 5.8 mg/ml of fructose, and 18 mg/ml of sodiumgluconate.

[0173] Peroxide primer (solution 3) contained: 500 ppm eosin in TEOAbuffer, plus 5 microliter/ml of 10% tertiary butyl peroxide. Analternative priming solution (3b) contained in addition 10% 35KL4.

[0174] Serial dilutions of one volume of iron monomer with two volumesof stock monomer were made, and the gelation time, in the absence ofhigh-intensity light, upon addition of 1 volume of priming solution (3)to two volumes of diluted iron monomer was determined. The stock ironmonomer and the 1:3 dilution gelled very rapidly (1-2 seconds), and a1:6 dilution gelled in 3-4 seconds. The 1:9 dilution gelled veryslowly—no rapid gelation, and partial gelation after 1 hour. Furtherdilutions (1:27, 1:81) did not gel for at least one hour.

[0175] The formulation with 1:9 dilution, containing about 2.2 mg/ml offerrous gluconate, was tested for its ability to adhere to excisedtissue, and to gel in the presence of blood. Acute adherence wasobtained with 1:9 iron monomer solution when primed with the basicperoxide priming solution, but better adherence was found withmonomer-containing priming solution (3b).

[0176] In solution, a mixture of monomer solution (0.3 ml) and normalprimer (0.13 ml; without peroxide), which polymerized when exposed tointense argon laser light, would not gel after addition of 2 drops ofblood (about 33 mg). However, a mixture of the same volumes of 1:9 ironmonomer, primer 3b, and blood gelled in 5 seconds on exposure to thesame light source. Omission of the Na gluconate and fructose did notsignificantly change the gel time. The mixed formulation (iron monomer,peroxide primer, and blood) could be held for three hours in amber glassat room temperature with only slight decrease in the gelling time onexposure to light.

[0177] Thus, the formulation is sufficiently stable and controllableunder operating room conditions, so that a preparation could bereconstituted at the start of the operation, and the material would beuseful and applicable to tissue throughout the operation.

EXAMPLE 14

[0178] Adherence to tissue at varied concentrations of peroxide andiron.

[0179] Areas of excised fresh or frozen-thawed pig lung were primed witha photoinitiator, and a gel formed on the spot by dripping ofphotoinitiator-containing monomer. In contrast to the previous example,the iron (ferrous gluconate) was in the primer, and the peroxide in themonomer solution. Gels formed by illumination at peroxide concentrationsranging from 76 to 900 ppm, and iron concentrations ranging from 1500 to5000 ppm, had at least moderate adherence to tissue after overnightincubations.

EXAMPLE 15

[0180] Redox interfacial primed system.

[0181] It was demonstrated that non-photopolymerization techniques canproduce gels adherent to tissue. Thinly-sliced ham was soaked indeionized water, and a 1 by 2 inch piece was folded in half and theouter edges were bonded together. First, 0.1 ml of solution A wasapplied to the joint (Solution A contained 10% monomer 8KL5, 0.3%hydrogen peroxide, and 0.3% NVMA (N-vinyl N-methyl acetamide)). Then 0.2ml of Solution B was applied. (Solution B contained 30% 8KL5, 20 mg/mlFerrous Ammonium Sulfate hexahydrate (Aldrich), 3% fructose, and 0.3%NVMA. Cure was instantaneous, and no discoloration of the gel occurred.The bond held during overnight soaking in distilled water.

EXAMPLE 16

[0182] Sprayed redox system.

[0183] Using the above solutions, and with monomer concentrationsvarying from 5% to 10% in solution A and 10% to 30% in solution B.primer (solution A) was sprayed on semivertical surfaces, followed bysolution B. Surfaces were the palm of the experimenter's hand, and petridishes. The spraying procedure caused some foaming, but gels were formedon all surfaces. Because of running of the solutions down the surfaces,gels were thicker at the bottom but present throughout In a similarexperiment, the monomer 8KTMC, containing trimethylenecarbonatebiodegradable linkages between the polyethylene glycol and the acrylatecap, seemed to adhere somewhat better than the 8KL5.

EXAMPLE 17

[0184] Comparison of peroxygen compounds.

[0185] Reductant solutions contained 10% 8KL5 monomer and 8% by volumeof a ferrous lactate solution, which itself contained 1% ferrous lactateand 12% fructose by weight in water. Oxidant solutions contained 10%8KL5 monomer and a constant molar ratio of oxidizer, which was, per mlof macromer solution, 10 microliters 30% hydrogen peroxide; 8.8microliters tert-butyl peroxide; 15.2 microliters cumene peroxide; or0.02 g potassium persulfate. 0.5 ml of reductant was mixed with 0.25 mloxidizer, and time to gelation was noted. With hydrogen peroxide,gelling was nearly instantaneous, while with the others there was ashort delay—about 1 second—before gelation. Doubling the t-butylperoxide concentration also produced nearly instantaneous gelling.Hydrogen peroxide produced more bubbles in the gel than the others;persulfate had almost no bubbles. The bubbles in hydrogen peroxide maycome directly from the reactant, as the other compounds have differentdetailed mechanisms of radical formation.

EXAMPLE 18

[0186] Effect of reducing sugars.

[0187] Using the procedures of Example 17, the concentration of ferrousion was reduced to 50 ppm, and the fructose was omitted. At 100 ppm HOOHin the oxidizing solution, gel time was increased to 3 to 4 seconds,with both Fe-gluconate and Fe-lactate, but gels were yellow Addition of125 ppm ascorbic acid to the reducing solution prevented the formationof the yellow color.

EXAMPLE 19

[0188] Sodium gluconate addition.

[0189] It was found that raising the pH of the iron-peroxide system from3.7 to 5.7 by addition of sodium gluconate had no effect on gelationtime.

EXAMPLE 20

[0190] Compatibility with ultraviolet photoinitiators.

[0191] Solution A contained 1 g 8KL5, 0.4 ml of a ferrous lactatesolution (containing 0.4 g ferrous lactate and 4.8 g of fructose in afinal volume of 40 ml of distilled water), and 8.6 g of distilled water.Solution B contained 1 g of 8KLS, 0.1 ml of 30% hydrogen peroxide, and8.9 g water. Drops of A were allowed to fall into a solution of B,resulting in drops of gel which gradually accumulated at the bottom ofthe solution. If solution B was supplemented with 4% by volume of asolution of 0.2 g of Irgacure™ 651 photoinitiator dissolved (withheating) in 4 ml of Tween™ 20 detergent, then after making bead dropletsas before, the entire solution could be gelled by application of UVlight. This demonstrates the compatibility of the redox and UV-curingsystems. Moreover, it would be possible to make the redox-cured dropletsfrom a monomer which would degrade either faster or slower than thecontinuous-phase gel, as desired, thereby potentially creating amacroporous gelled composite.

EXAMPLE 21

[0192] Relative adherence of gels.

[0193] Various gel formulas were compared in their ability to stick todomestic ham, versus their ability to adhere the fingers of the handtogether. It was found that adherence of a formula to one type ofsurface was only weakly predictive, at best, of the adherence to theother. In another experiment, it was found that persulfate-catalysedgels are less adherent to tissue than comparable t-butyl peroxide gels,but are relatively more adherent to metal. Thus, the optimal formulationmay well depend on what is to be coated with gel.

EXAMPLE 22

[0194] Intra-pleural sealing.

[0195] A source of morbidity in lungs is the formation of bullae, whichare sacs formed by separation of the plerua from the lung parenchyma. Asa model for possible repair of bullae, the pleura of a detached lung wasrepeatedly nicked to generate small air leaks. Then a solutioncontaining 15% of 35KL18 macromer, 20 ppm of eosin, 5 milligrams/mlvinylcaprolactam, and 90 mM triethanolamine was injected between thepleura and parenchyma at the sites of the air leaks. The solution spreadpreferentially between the tissue layers, forming a blister-likestructure. The area was transilluminated from the pleural side withblue-green light for 40 seconds. A flexible gel was obtained, and theair leaks were sealed.

[0196] A similar procedure could be applied to other layered tissues tostop leaks and effusion. Because the gel is confined within the tissue,adherence to tissue is not a primary concern. There are a number ofanatomical structures having layered tissue structures suitable for thismethod of sealing a tissue against leakage. Such tissue layers includethe meninges, including the dura, the pia mater and the arachnoid layer;the synovial spaces of the body including the visceral and pareitalpleurae, the peritoneum, the pericardium, the synovia of the tendons andjoints including the bursae, the renal capsule, and other serosae; andthe dermis and epidermis. In each case, a relatively fragile structurecan be sealed by injection of a polymerizable fluid between adjacentlayers, followed by polymerization. Formation of a biodegradable,biocompatible gel layer by non-intrusive processes such asphotopolymerization is especially desirable, because it minimizes traumato the tissue.

EXAMPLE 23

[0197] Sealing of an Injured Artery.

[0198] In an anesthetized pig, a 1.5 cm lengthwise incision was made ina carotid artery. The incision was closed with interrupted sutures, sothat blood seepage occurred. The injured area was rinsed with saline,and the blood was suctioned from the treatment zone. The treatment zonewas primed with 1 mg/ml eosin in buffer (TEOA in ⅓normal phosphatebuffered saline). A macromer solution was applied with a smallpaintbrush to the treatment zone under illumination with blue-greenargon ion laser light. In a first artery, the macromer solutioncontained 15% 35KC3.3, 4 mg/ml N-vinylcaprolactam, and 20 ppm eosin. Ina second artery, the macromer was type 35KL18, and-the macromer solutionhas a paste-like consistency. Four applications (0.5 to 1.0 ml each)were required to seal all leaks. It was easier to build thickness withthe paste-like monomer. The pig was held under anesthesia for an hour,and the injury sites were reexamined and found to be still sealed.

EXAMPLE 24

[0199] Adherence of coating layers to living tissue surfaces.

[0200] An experiment was performed to evaluate the acute adherence of aformulation of 20% macromer 35KTMC8A2 with redox/eosin primer touninjured tissue in situ. An immature pig (est. 35 kg) was maintained inan anesthetized condition and various tissues and prosthetic implants(described below) were surgically exposed or prepared. Care was taken toprevent injury to the tissues; however, the dissection of connectivetissue often resulted in a roughened surface where the primer/polymerwas applied.

[0201] The primer and macromer were applied with separate paint brushes,and light was delivered from a bare 2 mm diameter optical fiber. Thelight source was periodically checked and consistently emitted approx.580 mW of visible light through the course of the experiment at thedistal tip of the delivery fiber.

[0202] The acute adherence was graded on a 1-4 scale, where 3 or betteris considered acceptable:

[0203] “4”: cohesive failure into small pieces when the deposited gel isgripped with blunt tweezers and pulled perpendicular and/or parallel tothe tissue surface.

[0204] “3”: cohesive failure with larger fragments.

[0205] “2”: combined cohesive/adhesive failure.

[0206] “1”: adhesive failure, gel lifts off in continuous film.

[0207] A. Adherence to tissues (Tissue/adherence grade):

[0208] 1) Lower stomach (proximal to pylorus)—3.5 The stomach wasreexamined after 1 hour indwelling—<3.5. Still adherent, but less thanat time =0. Tear strength deteriorated.

[0209] 2) Common bile duct—3.5

[0210] 3) Urinary bladder—3.8 (Punctate bleeding was noted on thebladder; it was confirmed that the causes were brushes andmanipulation).

[0211] 4) Ureter—3.5-3.8;

[0212] 5) Large bowel (descending colon 8 cm anterior to pubic bone)—4.0

[0213] 6) Esophagus—3.5.

[0214] 7) Patellar tendon (2 cm proximal to tibial attachment)—3.5

[0215] 8) Cartilage (trochlea groove of knee)—2.5 This tissue didn'tstain with eosin; polymerized gel peeled off in sheets. Removal of upperhyaline layer, deep enough for minor blood oozing to appear, improvedscore to 2.8.

[0216] B. Adherence to other implantable materials.:

[0217] 9) Collagen coated Dacron patch—3. This was a Datascope wovenDacron graft material 8 mm diameter. Collagen impregnated; 6-0 Prolenesutures.

[0218] 10) Abdominal aortic graft—3.5. This was a Meadox Dacron doublevelour (inside/outside); 6 mm Inside diameter; Cat No. 174406. Lot No245246. Sterilized 1986. The graft was preclotted in autologous blood.The animal was heparinized before implantation.

[0219] 11) Gore FEP (fluorinated ethylene propylene) in vitro test—0.Material would not stain; cured polymer slid off without effort.

[0220] 12) Carotid Gore patch—2.5-3. Polymer adhered to sutures andsurrounding tissue.

[0221] 13) Hernia mesh—2.5 (more or less). Polymer was used to anchorthe mesh (by U.S Surgical) onto external abdominal oblique fascia. Thepolymer was suitable for positioning, but did not provide “structural”anchoring.

EXAMPLE 25

[0222] Process for sealing medical devices to body tissues.

[0223] There is a need to seal or bond medical device surfaces totissue. To be successful, this application requires the sealant oradhesive to form strong bonds to both the device and the tissue.Important examples of this application apply to sustained use devicessuch as percutaneous catheters (e.g. central venous catheters),percutaneous cannulae (e.g. for ventricular assist devices), urinarycatheters, percutaneous electrical wires, ostomy appliances, electrodes(surface and implanted) and the like. In such devices, there is atendency of the implant or device to move relative to the surroundingtissue. Such movement can allow entry of microorganisms, or canintensify the reaction of the tissue to the implant. Moreover, when adevice is inserted percutaneously, then during the process of healingthe epidermis in contact with the implant may undergo“marsupialization”, or the formation of a partial pouch along thesurface of the implant. This can retard healing of the percutaneousopening, following removal of the device.

[0224] In scope, the process includes sealing the device/tissueinterface for any medical device that crosses or disrupts a tissue layerwhose continuity provides a natural defense mechanism against infectionor bodily fluid loss (skin, mucous membranes). This technology is alsoapplicable to obliterating potential space between implanted devicesthat do not allow tissue ingrowth/ongrowth and the implant bed, servingto reduce device movement which is a cause of chronic inflammation.These tissue-device sealants may also serve as matrices for drugdelivery, for example the delivery of antimicrobials to preventinfection.

[0225] Bioabsorbable hydrogels and non-absorbable analogs are appealingfor these applications in that they may be formed in place to seal (or“caulk”) around the device. Hydrogels usually adhere poorly tohydrophobic device surfaces which comprise most of the examples listedabove.

[0226] However, a process is provided herein which produces a strongattachment of hydrogel to a hydrophobic surface during in situpolymerization of hydrogel components. It involves applying a primercontaining adequate concentrations of an initiator of polymerization(Eosin Y and/or other ingredients) to a hydrophobic surface (in theexample below, polystyrene, in a 12 well plate) following with a sealantcomposition based on a polymerizable macromer (in this examplecontaining triethanolamine co-initiator), and effecting polymerization.The different embodiments, 25.1-25.3, are described below.

[0227] 25.1: Into one well of a 12 well microtiter dish was placed 0.1ml of a primer solution containing 500 ppm eosin with ferrous gluconate(5 mg/ml), fructose (10 mg/ml), and macromer 3.3 KLSA2 (30%). Then 0.9ml was added of a solution containing 12.8% of macromer F127T4A2 (i.e.,poloxamer Pluronic F127, with 4 units of trimethylene carbonate andacrylate end caps), 125 ppm t-butyl peroxide, 90 mM triethanolamine and0.4% VC (N-vinylcaprolactam). The mixture partially gelled on mixing,but the gel was not coherent. After illumination with blue light for2×20 sec., a coherent gel was formed. However it was not tightly adheredto the surface of the plastic.

[0228] 25.2: The experiment was repeated, but the eosin concentrationwas raised to 2000 ppm. Initially the solution did not gel as well, buton illumination the gel adhered strongly to the plastic.

[0229] 25.3: The experiment was repeated at 2000 ppm eosinconcentrations, but without the “redox” components (ferrous gluconate,fructose, t-butyl peroxide). Adherence was stronger at 2000 ppm eosin(alone) than at 500 ppm even with redox materials, although not asstrong as with the redox components present.

[0230] The results are compatible with the idea that the eosin wasabsorbing to the surface of the plastic during the course of theexperiment. To validate this, a solution containing 12.8% macromer(F127T4A2), the usual VC and buffer, no redox components, and 2000 ppmeosin was applied to a well and allowed to stand for about 10 seconds.The gel was strongly adherent. In a comparable experiment at 100 ppmeosin, the gel was formed but adhered weakly.

[0231] Thus, a critical variable here appears to be the level ofphotoinitiator—here eosin—in the primer. Relatively high concentrations(2000 ppm) gave stronger bonds of hydrogel to polystyrene than loweramounts. The use of “redox” coinitiators gave stronger gels, but highEosin levels gave strong bonds with or without “redox” coninitiation.

[0232] In other experiments, it was demonstrated that the system thatgave the strongest bonds to the polystyrene also gave very strong bondsto animal tissue (cadaveric goat gingiva). The strong bonding of sealantto polystyrene 12 well plates may thus used (in the absence of tissue)todemonstrate the tissue bonding capability of a particular hydrogel, thusminimizing experimentation. This system, applied simultaneously to atissue and a hydrophobic device (via application of primer, sealant, andlight) would thus appear to result in an effective tissue-to-devicesealant with wide-ranging applicability.

EXAMPLE 26

[0233] Use of redox-assisted photoinitiation in treatment of injuredarteries.

[0234] The interior of a rabbit carotid artery was injured by scrapingwith an inflated balloon catheter. The injured area was then isolatedwith a two balloon catheter, and the injured zone was flushed withsaline;stained on its surface with an initiator solution, containing 20ppm eosin Y in PBS (phosphate-buffered saline, pH 7.4); further flushedwith saline to remove unbound eosin;treated with a buffered solutioncontaining 90 mM TEOA (triethanolamine), pH 7.4; 30% by weight ofpolymerizable macromer; 0.2% to 0.25% of vinylpyrrolidone orvinylcaprolactam; and optionally 50 ppm of ferrous sulfate. Thetreatment zone was then exposed to 100 mW/sq. cm. of green light from anargon laser for 20 seconds. The balloons were collapsed and blood flowwas permitted to resume, resulting in flushing of excess macromer fromthe zone into the rest of the circulation. In various tests, it wasfound that a thin layer of gel was formed on the inside of the arteryboth with and without the addition of ferrous ion. It was further foundthat the layer persisted for longer times in the presence of the ferrousion.

[0235] To better understand this system, gels were formed in test cells,and their mechanical properties after various lengths of illuminationwere compared. It was found that the addition of iron resulted in gelswhich were better cured and which were relatively less sensitive to theexact concentration of other reagents, or to the duration ofillumination. This is shown in more detail in Table 1: TABLE 1 Ratio ofModulus at 20 sec. to 90 sec. of illumination 20 100 Redox ppm ppmIllumination conc. eosin eosin 100 mW/cm2 50 ppm Fe 93% 83%  0 ppm Fe63% 14% 400 mW cm2 50 ppm Fe 98% 77%

[0236] Conditions: 30% 3.3KL5 in 90 mM TEOA pH 7.4 and 2 μL VP/mL

[0237] The ratio of the gel modulus at 20 sec. illumination to 90seconds is a measure of the rapidity of complete polymerization of thegel. Higher numbers denote faster polymerization. It can be seen thatthe addition of iron markedly accelerates the cure, and that this effectis more pronounced at 100 ppn eosin, where the underlying variation isgreater, and likewise at lower light levels.

EXAMPLE 27

[0238] Redox systems with Urethanes, Acids and Amides, using Ceric Ion.

[0239] The objective of the experiment was to determine the feasibilityof making polar-ionic macromers using a Ce-IV based redox system withurethanes, carboxylates or amides as reductant. A special macromer wasmade (3.3KL5Al: 3.3 K PEG; 5 lactides; 1 acrylate) and end-capped withdiisocyanate to form a urethane by standard procedures.

[0240] The different embodiments, 27.1-27.4, are described below.

[0241] 27.1: Add 1 ml of methacrylic acid to 10 ml of 2.25 wt. % Cericammonium nitrate in water (“Ce solution”; has yellow color). A whiteprecipitate was formed immediately; the yellow color faded over time.

[0242] 27.2: Add 10 ml Ce solution to a 10 ml solution containing 0.5 mlacetic acid and 0.5 ml methyl acrylate. A white precipitate formedimmediately, and the yellow color gradually faded.

[0243] 27.3: Add 1 g of the NCO-end capped initiator to 10 ml of Cesolution, and mix with 10 ml of a 50% w/v solution of AMPS (acrylamidomethyl propanesulfonic acid). The solution remained yellow andunprecipitated. However, after standing overnight at room temperaturethe solution had become colorless and highly viscous, and was notfilterable through a 0.2 micron filter. This suggests a high degree ofpolymerization, perhaps with some crosslinking.

[0244] 27.4: A carboxylate-terminated macromer was made by treating 3.3KL5A1.0 with succinic anhydride. The purified reprecipitated polymer wasdissolved in deionized water (0.39 g /7 ml) and 2.0 g of AMPS was added.The pH was adjusted to 3.8 with NaOH. Then 55 mg. of Ce(IV) ammoniumnitrate was added (approximately stoichiometric with the expected numberof carboxyl groups). The volume was adjusted to 10 ml. with water. Thesolution rapidly became turbid and increased in viscosity, and appearedto be crosslinked to a gel within about 1 hr. The resulting gel could bedissolved by pH 13 NaOH solution in about 1 hr., showing that thecrosslinks involved the degradable ester moieties.

[0245] It appeared that both carboxylic groups and urethane groups canserve as reductants for ceric ion in a redox-catalysed polymerization ofan unsaturated group. Other groups known to be effective in suchreactions can also be used where the conditions are physiologicallyreasonable.

EXAMPLE 28

[0246] Adherence of medical device material to tissue.

[0247] In this example, direct adhesion of a typical medical polymer totissue is demonstrated. It is further shown that the location of theplane of fracture of the composite can be controlled by selection ofconcentration and type of photoinitiator.

[0248] Microscope-slide-sized pieces of Pellethane (Dow) extrudedpolyurethane sheet were washed with acetone to remove impurities anddried in a vacuum oven. They were then stained with a solution of 2000ppm Eosin Y in PBS, as above, for several minutes until pink staining ofthe polyurethane was observed. Sheets were rinsed in water and airdried.

[0249] Pieces of abdominal wall were excised from a euthanized rat, andused with the peritoneal side “up” (“tissue”). Tissue was clamped to aglass slide with binder clips. Thin Teflon spacers were placed on top ofthe tissue. Dried sheets of urethane were clamped into the sandwich,eosin-stained side towards the tissue, forming a thin chamber betweenthe polyurethane and the tissue, typical of clearances found in medicalpractice. Four combinations of solutions were tested.

[0250] The different embodiments, 28.1-28.4 are described below.

[0251] 28.1: About 0.2 ml of a primer solution containing 2000 ppm eosinin PBS was infused into the chamber, and was removed by wicking afterabout a minute. A macromer solution (about 0.2 ml) was added, containing12.8% F127T4A2 macromer (as in example 27), 90 mM TEOA and 0.4% VC(vinyl caprolactone), and, in this experiment, 2000 ppm eosin. Thechamber was transilluminated through the glass slide and rat flap for 40seconds. The macromer did not completely polymerize, and on removal ofthe clamps the tissue separated from the urethane without appreciableforce.

[0252] 28.2: The above experiment was repeated, but the eosinconcentration in the macromer solution was reduced to 20 ppm.Polymerization was complete. On separation of the tissue from theurethane, the gel fractured while remaining adherent to both tissue andto the urethane.

[0253] 28.3: The above experiment 28.2 was repeated, except that theredox accelerator t-butyl peroxide was present in the macromer solutionat 125 ppm, and the primer contained Ferrous gluconate and fructose asin Example 25.1. The gel was completely polymerized. On attempting topeel the tissue from the urethane, the tissue tore—i e., both the geland its bonds, to both tissue and device, were stronger than the tissueitself.

[0254] 28.4: Experiment 28.2 was repeated, except that the concentrationof eosin in the primer was reduced to 20 ppm. Polymerization wascomplete. On peeling the tissue, failure of adhesion occurred at theinterface between the gel and the tissue.

[0255] This example demonstrates that by selection of initiator typesand concentrations, the fracture plane of a device bonded to a tissue bya gel can be varied at will, and behaves in a reasonable and predictableway. Although the gel compositions in this example were degradable, thepeeling was done at short times, and the results will extrapolatedirectly to non-degradable gels.

[0256] In the following Examples 29-30, the following methods andparameters were used:

[0257] Elongation to fracture and Young's or other elastic modulus.

[0258] Samples are prepared in a mold to have the required concentrationof monomer and other ingredients. The crosslinked or otherwise curedspecimens are placed in an appropriate machine, such as an Instron™tester, and the force required to stretch the sample along a single axisis measured as a function of the distance the sample is stretched(strain). Elongation may be continued until the sample breaks, givingthe value for elongation at break, optionally after cycling at lowerelongations to determine the degree of any plastic deformation of thesample. The data (force vs. distance) may be recorded and used to make aplot, as in FIG. 1 Because the response of a particular material is notnecessarily “ideal”, especially at high elongation, a modulus may becalculated from values at low degrees of elongation where the behavioris closer to linear. Alternatively, the force vs. strain values may beused directly without extrapolation, or without division by samplethickness to give the “normalized compliance” discussed above.

[0259] Bulk Compression Modulus.

[0260] The sample of gel or tissue is placed in a suitable instrument,such as a Perkin-Elmer DMA 7e, and the modulus is measured according toa standard procedure. A gel sample could also be polymerized directly inthe instrument for testing.

[0261] Adhesive strength.

[0262] This was tested by a lap shear test. The test sealant materialwas used to adhere a 1 cm×1 cm area of two pieces of test substrate,typically a standardized tissue such as rat peritoneum or pigpericardium. After crosslinking or curing of the test material, theforce required to break the adhesive bond was determined using asuitable instrument, such as an Instron™ tester. In one variant of thetest, three pieces of substrate were adhered: a center piece, with tabextending in one direction, and a pair of outer pieces with tabsextending in the opposite direction; sealant was used to join all threepieces. Either arrangement also can be used to determine the relativemechanical properties of various samples (i.e., compared to standards)at small displacements, which is useful when only limited sample volumeis available

[0263] Adherence

[0264] Adherence of sealant formulae in vivo is determinedqualitatively, by the relative resistance of the sealant to displacementfrom its deposition site by a probe.

[0265] Viscosity

[0266] Viscosity was measured by standard methods, typically in aBrookfield™ viscometer.

[0267] Seal Pressure Testing

[0268] Seal Pressure Testing was performed by punching a 3 mm round holein a standard tissue, such as pig pericardium, and mounting the tissueas the closure in a test fixture. Sealant was applied to the hole andcured, typically in a spiral pattern, to obtain closure of the hole.Then increasing pressure was applied to the transverse side of thetissue until the plug of sealant was displaced.

[0269] Sealant Polymerization

[0270] In Examples 29-30 below, a preferred formulation of the sealingsystem was used. When applied to tissue or to a surface to whichadherence was required, the surface was primed with a mixture whichcontained by weight approximately 65% water, 30.4% of a polymerizablemacromer (3.3KL5A2, a 3.5 kD polyethylene glycol backbone carrying anaverage of 5 lactate groups and end capped with acrylate), 3% NaCl, 1%fructose, 0.5% ferrous gluconate, and 0.2% Eosin Y. The primer wasapplied to the surface and spread with a brush. Then about 2 volumes ofsealant solution was applied and mixed with a brush. The sealantcontained about 77% water, 20.5% polymerizable macromer 35KTMC8A2 (35 kDpolyethylene glycol carrying an average of 8 trimethylenecarbonategroups and end capped with acrylate), 1.1% triethanolamine, 1% KH2PO4,0.4w vinylcaprolactam, 0.013% t-butyl hydroperoxide, and 0.002% Eosin Y.When the sealant solution was tested in isolation, the t-butylhydroperoxide was omitted. The sealant system was photopolymerized byexposure to blue-green light for about 40 sec.

EXAMPLE 29

[0271] Elasticity Results.

[0272] Using the materials described above, lap shear testing sampleswere prepared by applying the macromer solution-with a cotton swab to a1 cm×1 cm area on a 3 cm×1 cm strip of rat peritoneal tissue, thenlaying the other strip of the same size on top as to make a sandwich.The sample was then transilluminated from the top and then the bottomfor 40 sec each. Lap shear testing was performed using a 12.5 mm gaugelength. Tensile testing using a sample size of 45 mm×10 mm×5 mm and a12.5 mm gauge length, was performed. DMA (Perkin Elmer) testing with asample height of 1.6 mm was performed at 37° C. after hydrating for 2hours in saline at 37° C. A subjective scoring system was used to assessadherence in a goat lung model on a scale from 1-4 (1=poor adherence &4=excellent adherence).

[0273] In Vitro Testing

[0274] This synthetic surgical sealant could be rapidly polymerized withvisible light to form a flexible hydrogel. As can be seen from thetensile data in FIG. 1, this material showed a completely elasticdeformation profile with linear elongation at break in excess of 700%.The polymerization process of this material and the properties of lungtissue and muscle tissue were studied using the dynamic mechanicaltester. It was seen that muscle tissue, as expected, had a highermodulus than spongy parenchymal lung tissue. The sealant material wascured within 40 seconds and reached a final modulus very comparable tothat of the lung tissue. This ensures a compliant and persistentadhesive bond. The bond strength was determined using the lap shear testapparatus and the material was seen to form a strong yet flexible bondto tissue. This bond strength is in excess of literature values forfibrin glues in comparable tests. Table 1 shows a summary of in vitroresults.

[0275] In Vivo Testing

[0276] All goats that had undergone the thoracotomy procedure survivedthe surgery uneventfully. Goats were sacrificed at timepoints of 14days, 1 month, and 3 months. At all timepoints, the hydrogel was seen tobe firm and clear and had an adherence score of 3.0-3.5 out of 4.0. Notissue necrosis was evident. Histological sections of the tissue showednormal healing. The results are shown below in Table 2. TABLE 2 In-VitroTesting Summary Property; Result Compressive modulus at full cure,sealant; 32.4 kPa Compressive modulus of lung tissue, pig; 27.5 ± 3.4kPa Compressive modulus of lung tissue, dog; 28.0 ± 1.9 kPa Modulus ofrat muscle tissue; 73.4 ± 6.8 kPa Young's modulus at full cure, sealant;29.4 kPa Elongation at break, sealant; 788 ± 255.2% Sealant lap shearstrength; 90.17 ± 18.17 g/cm²

EXAMPLE 30

[0277] Comparative Results.

[0278] Tissucol™ sealant is a commercial fibrin sealant used in Europe.It is not at present approved for use in the United States, in partbecause it is made from human serum and thus may carry infectiousagents. Tissucol sealant was used according to its manufacturer'sdirections. In comparison to the preferred sealant formulation of theprevious example, the following results were obtained shown in Table 3:TABLE 3 Properties of Sealants FocalSeal ™ Tissucol ™ Test: SealantSealant A. Double lap shear 38 ± 6 kPa 10 ± 6 kPa B. Compression Modulus32 ± 1 kPa 35 ± 5 kPa C. Viscosity ≈780 cP at 20% 117 cP conc.(fibrinogen) 1.6 CP (thrombin) D. Seal Pressure Test ≈380 ± ≈30 ± 100 mmHg 20 mm Hg

[0279] When applied to a living dog lung, the fibrin sealant had anadhesion score of 1, and leaked on all staple lines at 10-40 mm Hg. Itwas difficult to apply the fibrin material to a punch-type leak, becauseair bubbles coming through the leak tended to remove the material beforeit polymerized. In contrast, sealant adhered to primed tissue with anadhesion of 3.5, and typically withstood 80 mm Hg or more of pressure.Its high viscosity slowed bubble penetration.

[0280] The optimal material for lung, as described above, has anelongation at break of over 700%. Other materials were suitable, if lessoptimal. For non-collapsed lung, a material (20KT8A2) with an elongationat break of 225% was suitable, while a material (8KLSA2) with anelongation at break of 100% (and an elastic modulus of 47±4 kPa) was noteffective in lung. The expansion of a dog lung was measured. It wasfound that the effective area expansion during a normal breathing cycleis about 200%, while the expansion from the atalectatic (collapsed)state to full inflation changed area by about 300%. In the latter case,an extension (strain) of about 100% was observed along one axis, andabout 200% along a perpendicular axis, implying non-uniformity of thetissue structure.

[0281] Thus, an important requirement for a sealant system on thistissue appears to be that the normalized compliance of the sealant isgreater than the normalized compliance of the tissue to which it isapplied. While the lung is perhaps the most dramatic example of tissueelasticity and area expansion during normal physiological processes,other tissues, such as the bowels, the bladder and large arteries, canchange surface area substantially during normal physiological cycles.Other tissues, such as the beating heart, exhibit significant changes inshape (shear) without necessarily changing local area.

[0282] The compliance of the sealant may be selected depending on thetissue to which it is to be applied. A sealant having a high value ofnormalized compliance, or a low value of the normalized compliance ratio(tissue /material), may be beneficial for certain applications. Forexample, the 700%—elongation low-modulus material described above isalso suitable for sealing the dura of the brain, or the spinal cordafter laminectomy, even though these tissues are relativelynon-compliant (i.e., are difficult to stretch). Thus, high normalizedcompliance sealant appears to be useful on most tissues, and desirableas a material having a broad range of applications.

What is claimed is:
 1. A compliant polymeric material on a tissuesurface, wherein the material is formed by the polymerization of anaqueous solution or suspension of a polymerizable monomer in contactwith the tissue surface, and wherein the normalized compliance ratio ofthe tissue and the material is in the range of about 0.05 to about
 3. 2.The material of claim 1 wherein the compliant material is a hydrogel,wherein the monomer is a photopolymerizable, biodegradable,water-soluble block copolymer comprising photopolymerizable groups, andwherein the monomer is polymerized in the presence of a free radicalpolymerization initiator.
 3. The material of claim 1 wherein thepolymerized material has an elongation at rupture which is similar to orgreater than the elongation of the tissue in vivo.
 4. The material ofclaim 1 wherein the polymerized material has an elongation at rupturewhich is greater than about 100%.
 5. The material of claim 1 wherein thepolymerized material has an elastic modulus which is less than about 150kPa.
 6. The material of claim 1 wherein the material has an adherence tothe surface of at least about 20 grams per square centimeter.
 7. Thematerial of claim 1 wherein the material further comprises abiologically active material.
 8. The material of claim 1 , wherein thematerial is biodegradable.
 9. The material of claim 1 wherein thematerial forms a sealant on a tissue surface.
 10. The material of claim1 wherein the material adheres two surfaces together, and wherein atleast one of the surfaces is a tissue surface.
 11. A kit for thepreparation of the compliant material of claim 1 , comprising one ormore containers each containing one or more of a polymerizable monomer,a priming material and an initiator of polymerization.
 12. A method forforming a compliant polymeric material on a tissue surface, the methodcomprising applying an aqueous solution or suspension of a polymerizablemonomer to the surface; and polymerizing the material on the surface;wherein the normalized compliance ratio of the tissue and the materialis in the range of about 0.05 to about
 3. 13. The method of claim 12wherein the material further forms a sealant on the tissue surface. 14.The method of claim 13 wherein the monomer is a photopolymerizable,biodegradable, water-soluble block copolymer comprisingphotopolymerizable groups, and wherein the method comprisesphotopolymerizing the monomer on the tissue surface in the presence of afree radical polymerization initiator.
 15. The method of claim 12wherein the polymerized material has an elongation at rupture which issimilar to or greater than the elongation of the tissue in vivo.
 16. Themethod of claim 12 wherein the polymerized material has an elongation atrupture which is greater than about 100%.
 17. The method of claim 12wherein the polymerized material has an elastic modulus which is lessthan about 150 kPa.
 18. The method of claim 12 wherein the material hasan adherence to the surface of at least about 20 grams per squarecentimeter.
 19. The method of claim 12 wherein the material furthercomprises a biologically active material.
 20. The method of claim 12 ,wherein the material is biodegradable.
 21. The method of claim 19wherein the method comprises applying the polymerizable monomer and thebiologically active material to the surface of a biological tissue andpolymerizing the monomer on the tissue to form a polymeric compliantmaterial on the surface incorporating the biologically active material,wherein the material is capable of controlled release of thebiologically active material.
 22. The method of claim 12 wherein thepolymerizable monomer is applied to a plurality of surfaces, at leastone of said surfaces being a tissue surface, and wherein thepolymerization of the material on the surface causes adhering of thesurfaces.
 23. The method of claim 13 wherein the compliant polymericmaterial is formed on the surface of a lung in vivo.